Progenitor endothelial cell capturing with a drug eluting implantable medical device

Abstract

A medical device for implantation into vessels or luminal structures within the body is provided, which stimulates positive blood vessel remodeling. The medical device, such as a stent and a synthetic graft, is coated with a pharmaceutical composition consisting of a controlled-release matrix and one or more pharmaceutical substances for direct delivery of drugs to surrounding tissues. The coating on the medical device further comprises a ligand such as a peptide, an antibody or a small molecule for capturing progenitor endothelial cells in the blood contacting surface of the device for restoring an endothelium at the site of injury. In particular, the drug-coated stents are for use, for example, in balloon angioplasty procedures for preventing or inhibiting restenosis.

What is claimed is: 
     
       1. An implantable medical device having comprising a luminal surface and a coating; wherein the coating comprises one or more layers of a biocompatible non-polymer matrix: one or more pharmaceutical substances for extended or controlled release to adjacent tissue, and a ligand covalently attached to said matrix and operably configured to capture circulating endothelial progenitor cells on the luminal surface of said device after implantation of said medical device into a patient; wherein the non-polymer matrix is formed of a porous material comprising nanoparticles, wherein the nanoparticles comprise a metal, or a metallic alloy, and wherein the ligand comprises an antibody, an antibody fragment or combinations thereof. 
     
     
       2. The implantable medical device of  claim 1 , wherein the medical device is a stent, a vascular graft, a synthetic graft, a heart valve, a catheter, a vascular prosthetic filter, a pacemaker, a pacemaker lead, a defibrillator, a patent foramen ovate (PFO) septal closure device, a vascular clip, a vascular aneurysm occluder, a hemodialysis graft, a hemodialysis catheter, an atrioventricular shunt, an aortic aneurysm graft device or components, a venous valve, a sensor, a suture, a vascular anastomosis clip, an indwelling venous or arterial catheter, a vascular sheath and a drug delivery port. 
     
     
       3. The implantable medical device of  claim 1 , wherein the ligand is selected from the group consisting of an antibody, an antibody fragment or combinations thereof: proteins; peptides; and small molecules. 
     
     
       4. The implantable medical device of  claim 1 , wherein the ligand said antibody, antibody fragment or combinations thereof has specificity to and binds an antigen or cell membrane molecule selected from the group consisting of CD133, CD45, CD34, CD31, CD14, CDw90, CD117, VEGFR-1, VEGFR-2, Muc-18 (CD146), CD130, stem cell antigen (Sca-1), stem cell factor 1 (SCFc-Kit ligand), Tie-2, MHC H-2Kk and HLA-DR. 
     
     
       5. The implantable medical device of  claim 1 , wherein the non-polymer matrix is formed of said nanoparticles forming porous openings of from about 5 nm to about 5 microns in diameter and the ligand is an antibody, antibody fragments or combinations thereof. 
     
     
       6. The implantable medical device of  claim 5 , wherein the antibody or antibody fragment is anti-CD34 or anti-CD133. 
     
     
       7. The implantable medical device of  claim 1 , wherein the one or more pharmaceutical substance(s) is/are selected from the group consisting of vasodilators, antibiotics/antimicrobials, antiproliferative agents, antineoplastic agents, antioxidants, endothelial cell growth factors, smooth muscle cell growth and/or migration inhibitors, thrombin inhibitors, immunosuppressive agents, anti-platelet aggregation agents, collagen synthesis inhibitors, therapeutic antibodies, nitric oxide donors, antisense oligonucleotides, wound healing agents, therapeutic gene transfer constructs, peptides, proteins, extracellular matrix components, thrombolytics, anti-metabolites, growth factor agonists, antimitotics, steroids, steroidal antiinflammatory agents, chemokines, proliferator-activated receptor-alpha agonists, proliferator-activated receptor-delta agonists; proliferator-activated receptor-gamma agonists, nonsterodial antiinflammatory agents, angiotensin converting enzyme(ACE) inhibitors, free radical scavangers, inhibitors of the CX3CR1 receptor and anti-cancer chemotherapeutic agents. 
     
     
       8. The implantable medical device of  claim 1 , wherein said one or more pharmaceutical substance(s) is/are selected from the group consisting of peroxisome proliferator-activated receptor-alpha agonists, peroxisome proliferator-activated receptor-delta agonists, peroxisome proliferator-activated receptor-gamma agonists, calcitonin gene related peptide (.alpha.-CGRP), monocyte chemoattractant protein-1, adenosine, prostacyclins, tachykinins, sialokinins, neurokinins, aromatase inhibitors, plasminogen activator, erythropoietin, darbepotin, serine proteinase-1 (SERP-1), and metalloproteinases. 
     
     
       9. The implantable medical device of  claim 7 , wherein said vasodilators comprise from about 1 to about 99% (w/w) of the composition. 
     
     
       10. The implantable medical device method of  claim 7 , wherein said coating on said medical device comprises multiple layers comprising one or more vasodilators. 
     
     
       11. A method for treating vascular disease, comprising implanting into a patient in need of treatment a medical device having a luminal surface and a biocompatible coating; wherein the coating comprises a non-polymer matrix; one or more pharmaceutical substances and a ligand covalently attached to said matrix and operably configured to capture circulating progenitor cells on the luminal surface of said medical device after implantation into said patient; wherein the non-polymer matrix is formed of a porous material comprising nanoparticles, selected from a size of about 5 nm to about 5 micron in diameter and wherein the nanoparticles comprise a metal, or a metallic alloy. 
     
     
       12. The method of  claim 11 , wherein the ligand comprises an antibody, an antibody fragment or combinations thereof, proteins, peptides, or small molecules. 
     
     
       13. The method of  claim 11 , wherein the ligand has specificity to and binds an antigen selected from the group consisting of CD133, CD45, CD34, CD31, CD14, CDw90, CD117, HLA-DR, VEGFR-1, VEGFR-2, Muc-18 (CD146), CD130, stem cell antigen (Sca-1), stem cell factor 1 (SCF/c-Kit ligand), Tie-2, and MHC H-2Kk. 
     
     
       14. The method of  claim 11 , wherein the non-polymer matrix is formed of nanoparticles forming porous openings of from about 5 nm to about 5 micron in diameter and the ligand is an antibody, antibody fragments or combinations thereof. 
     
     
       15. The method of  claim 14 , wherein the antibody or antibody fragment is anti-CD34 or anti-CD133. 
     
     
       16. The method of  claim 11 , wherein the one or more pharmaceutical substance(s) is/are selected from the group consisting of vasodilators, antibiotics/antimicrobials, antiproliferative agents, antineoplastic agents, antioxidants, endothelial cell growth factors, smooth muscle cell growth inhibitors, smooth muscle cell migration inhibitors, thrombin inhibitors, immunosuppressive agents, anti-platelet aggregation agents, collagen synthesis inhibitors, therapeutic antibodies, nitric oxide donors, antisense oligonucleotides, wound healing agents, therapeutic gene transfer constructs, peptides, proteins, extracellular matrix components, thrombolytics, anti-metabolites, growth factor agonists, antimitotics, steroids, steroidal antiinflammatory agents, chemokines, proliferator-activated receptor-alpha agonists, proliferator-activated receptor-delta agonists; proliferator-activated receptor-gamma agonists, nonsterodial antiinflammatory agents, angiotensin converting enzyme(ACE) inhibitors, free radical scavengers, inhibitors of the CX3CR1 receptor and anti-cancer chemotherapeutic agents. 
     
     
       17. The method of  claim 11 , wherein said one or more pharmaceutical substance(s) islare selected from the group consisting of peroxisome proliferator-activated receptor-alpha agonists, peroxisome proliferator-activated receptor-delta agonists, peroxisome proliferator-activated receptor-gamma agonists, calcitonin gene related peptide (.alpha.-CGRP), monocyte chemoattractant protein-1, adenosine, prostacyclins, tachykinins, sialokinins, neurokinins, plasminogen activator, erythropoietin, darbepotin, serine proteinase-1 (SERP-1) and metalloproteinases. 
     
     
       18. The method of  claim 16 , wherein said vasodilators comprise from about 1 to about 99% (w/w) of the composition. 
     
     
       19. The method of  claim 16 , wherein said coating on said medical device comprises multiple layers comprising one or more vasodilators. 
     
     
       20. The method of  claim 11 , wherein said medical device is a stent, a vascular graft, a synthetic graft, a heart valve, a catheter, a vascular prosthetic filter; a pacemaker, a pacemaker lead, a defibrillator, a patent foramen ovale (PFO) septal closure device, a vascular clip, a vascular aneurysm occluder, a hemodialysis graft, a hemodialysis catheter, an atrioventricular shunt, an aortic aneurysm graft device or components, a venous valve, a sensor, a suture, a vascular anastomosis clip, an indwelling venous or arterial catheter, a vascular sheath and a drug delivery port. 
     
     
       21. The method of  claim 11 , wherein said disease is artherosclerosis, restenosis, or blood vessel occlusion. 
     
     
       22. The method of  claim 11 , wherein said one or more pharmaceutical substance(s) induces the formation of endothelium on the luminal surface of the device at the site of blood vessel injury. 
     
     
       23. The method of  claim 11 , wherein said one or more pharmaceutical substance(s) inhibits smooth muscle cell migration and/or proliferation. 
     
     
       24. An implantable medical device comprising a lumen and a luminal surface, said luminal surface comprising a biocompatible coating comprising one or more layers of a non-polymer matrix, formed of a porous material comprising nanoparticles; wherein the nanoparticles comprise a metal, or a metallic alloy and a therapeutically effective amount of a single type of antibody, antibody fragments or combinations thereof covalently attached to said one or more layers of said non-polymer matrix, and being compatible to binding selectively a specific cell surface antigen of circulating autologous endothelial progenitor cells in peripheral blood; and capturing the endothelial progenitor cells on the luminal surface of the device in vivo; wherein said coating releases said pharmaceutically acceptable intimal growth inhibitory substances on the external surface of said medical device and stimulates adherence and growth of said endothelial progenitor cells on the luminal surface of said medical device to rapidly form a confluent endothelium in situ. 
     
     
       25. The implantable medical device of  claim 24 , wherein the non-polymer matrix is formed of said nanoparticles forming porous openings of about 5 nm to about 5 micron in diameter. 
     
     
       26. The implantable medical device of  claim 24 , wherein said coating further comprises a biocompatible a polymer matrix with embedded pharmaceutical substances for extended or controlled delivery to adjacent tissue at a site of implantation. 
     
     
       27. The implantable medical device of  claim 24 , wherein said coating comprises one or more layers of a polymer matrix comprising elastin, tropoelastin, cross-linked tropoelastin or combinations thereof. 
     
     
       28. The implantable medical device of  claim 24 , wherein the polymer matrix comprises a biodegradable polymer of a polyester selected from the group consisting of poly lactic acid, polyglycolic acid, poly(L-lactide), poly(D,L-lactide), poly(D,L-lactic acid-co-glycolic acid); copolymers thereof and mixtures thereof. 
     
     
       29. The implantable medical device of  claim 24 , wherein the medical device is a vascular stent. 
     
     
       30. The implantable medical device of  claim 24 , wherein the antibody or antibody fragment is anti-CD34.